Introduction to Tolerance, Physical Dependence and Withdrawal

Introduction to Tolerance, Physical Dependence and Withdrawal

Carrie G Markgraf, MD, PhD

Safety Assessment Merck Research Laboratories

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Overview

? Definitions ? Addiction, psychological dependence, physical dependence (acute and protracted), tolerance, withdrawal ? Discrete and different phenomena that are often confused

? Regulatory status for assessment of dependence ? EMA, FDA, ICH

? Scientific insights into occurrence of dependence ? System level; neuronal level

? Class-specific withdrawal syndromes ? Benzodiazepines, stimulants, cannabinoids, opiates, alcohol

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Addiction ? Word Choice Matters!

? "Addiction" is a complex, multi-faceted concept ? Primary chronic neurobiologic disease ? Genetic, psychosocial and environmental factors ? Characterized by 1 or more behaviors: ? Impaired control over drug use ? Compulsive use, despite harm ? Hallmark is drug craving

? Dependence can be part of addiction, but is not the same thing ? Psychological dependence

? Drug/substance abuse, addiction, craving, relapse (key element is emotional need)

a: American Academy of Pain Medicine, American Pain Society, American Society of Addiction Medicine definition

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Physical Dependence

? A state of neuroadaption manifested by a drug-class specific withdrawal syndrome ? Defined following cessation of drug-taking

? Can be evidenced by appearance of withdrawal ? Abrupt cessation of dosing ? Rapid dose reduction ? Decreasing bio-availability ? Use of an antagonist

? Is an expected occurrence in all individuals in the presence of continuous use of many CNS-active drugs, particularly opioids, for days or weeks

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Tolerance

? Pharmacologic definition ? Resistance or decreased responsiveness to expected actions of a drug ? Higher or more frequent dosing to achieve initial effects of drug ? Tolerance does not imply addiction

? Clinical definition ? A state of adaptation in which exposure to a drug induces changes that result in a diminution of one or more of the drug's effects over time

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